Candida species are the fourth most common cause of nosocomial blood stream infections, and C. albicans accounts for 50% to 75% of Candida species in essentially all studies. Despite appropriate antifungal therapy, mortality is 35% to 75%. Patients at highest risk include immunosuppressed patients, trauma patients, and postsurgical patients, and a large proportion of cases occur in intensive care units. C. albicans undergoes reversible morphologic switching, producing budding yeast and filamentous forms that include germ tubes, pseudohyphae and true hyphae. Many investigators have assumed that filamentous forms are responsible for epithelial invasion. However, recent data from mouse models of extraintestinal dissemination indicate that the yeast cell, rather than filamentous forms, might be more important in C. albicans penetration of intestinal epithelium. Our working hypothesis is that yeast cells play a key role in interactions (adherence and penetration) of this fungus with the intestinal epithelium. The general approach is to use wild type and well-characterized C. albicans mutant strains (with defects in morphologic switching) to challenge this hypothesis in vitro (cultured enterocytes) and in vivo (mouse models). Because C. glabrata has recently emerged as the second most frequent cause of candidiasis, and because C. glabrata is the only species (of the more than 80 recognized Candida species) that does not form filaments and exists only in the yeast form, experiments also focus on C. glabrata. In vitro experiments are designed to separately characterize the interactions (adherence, internalization, intracellular survival) of yeast and filamentous forms with cultured enterocytes, and assay systems include ELISA and a double fluorochrome assay using calcoflour and the vital dye FUN-1. Mouse models include antibiotic-induced intestinal Candida colonization, ligated intestinal loops, and the Stamper-Woodruff assay. The effect of bacterial cell wall products (lipopolysaccharide and peptidoglycan), dexamethasone, and hypoxia on extraintestinal dissemination of Candida is also clarified. If our hypothesis is validated (that the yeast cell is of primary importance in extraintestinal dissemination), then efforts to design more effective in vitro susceptibility assays, as well as more effective prophylactic and therapeutic modalities, might more reliably target yeast rather than hyphal elements. Such knowledge should accelerate our ability to diagnose, treat, and control systemic candidiasis.